Objective To explore the mechanism of Xinguan No.0 against COVID-19 by network pharmacology combined with molecular docking. Methods The chemical components and targets of TCM contained in Xinguan No.0 were screened by TCMSP database，and the predicted targets of COVID-19 were screened by Genecards database. The two of them were mapped to obtain the key targets of Xinguan No.0 for prevention and treatment of COVID-19. The genes corresponding to the target were corrected by Uniprot database，and Cytoscape 3.8.2 was used to construct the Xinguan No.0-compound-COVID-19 target network. The protein interaction network was mapped by String database，and GO annotation and KEGG pathway enrichment analysis of key targets were performed by David database. Auto Dock Vina was used to conduct molecular docking between SARS-CoV-2 as the core receptor and the core components screened by Xinguan No.0 for verification. Results A total of 71 active compounds，including 249 composition-related targets，438 COVID-19 related targets and 58 drug-disease common targets were screened by Xinguan No.0. A total of 2180 GO items （P < 0.05） were obtained by GO functional enrichment analysis，including 2015 biological process （BP） items，41 cell composition （CC） items and 124 molecular function （MF） items. KEGG pathway enrichment analysis obtained 166 signaling pathways （P < 0.05），which were related to AGE-RAGE signaling pathway in diabetic complications，human cytomegalovirus infection，neurodegenerative pathways-multiple disease pathways，and multiple viral and inflammation-related pathways. Molecular docking showed that quercitin，luteolin and iridone in Xinguan No.0 had strong binding ability to novel coronavirus target SARS-CoV-2，which might be the potential active components of Xinguan No.0 against COVID-19. Conclusion The active compounds in Xinguan No.0 could regulate multiple signaling pathways by binding with SARS-Cov-2 to multiple targets，thus played a role in preventing and treating COVID-19.